CURRICULUM VITAE

DR. Dr. J. NUGROHO E. P, Sp.JP(K) , FIHA, FAsCC, FICA, FESC

J. Nugroho E.P was born in Yogyakarta-Indonesia and is the
staff of the Cardiovascular Department Dr. Soetomo General
Hospital.
Education :
1992 : Medical degree, Gajah Mada University, Jogjakarta-Indonesia
2003 : Cardiovascular Specialist, Airlangga University, Surabaya- Indonesia Cardiologist certification by
National Board of Examination, The Indonesian Heart Association
2013 : Vascular consultant by National Board of Certification/ Collegiums of Cardiology & Vascular
Medicine)
2014 : Doctoral degree, Airlangga University, Surabaya - Indonesia
Training in board :
2005 : ECHO Singapore
2007 : Singapore, Cardiac CT Course
2007 : Peripheral Computed Tomography, UCLA, los Angeles
2010 : Cardiac MRI Siriraj Hospital Bangkok, Thailand
2011 : Vascular Training, Harapan Kita National Heart Centre, Jakarta
2012 : Echocardiography and Vascular Training in Philipine Heart Centre, Quezon City
2013 : Fellowship on Intermediate Interventional Cardiology, Dr. Soetomo Teaching Hospital Faculty of
Medicine Airlangga
Memberships:
Member Indonesian Medical Association
Member Indonesian Heart Association
Fellow of ASEAN Federation of Cardiology (FAsCC)
Fellow International college of Angiology (FICA)
Fellow European Society of Cardiology (FESC)
 New Era in DVT Management :
Single Drug Approach

J. Nugroho, MD, Ph.D., SpJP (K),FIHA, FAsCC, FICA, FESC

Department of Cardiology and Vascular Medicine

Faculty of Medicine, Airlangga University -
Dr.Soetomo General Hospital
Surabaya-Indonesia
 Definition of DVT

Deep vein thrombosis

is the formation of a
blood clot in one of
the deep veins of the
body, usually in the
leg
 Deep Vein Thrombosis

Untreated Proximal DVT

Treated DVT
30-50% risk PE 15%
- <8% risk PE, Death
12-15% mortality - Mortality <2%
 The promise of new oral
anticoagulants
Simplified dosing regimen
No dietary restrictions Reduced potential
Predictable anticoagulation and no need for food and drug
for routine coagulation monitoring interactions
Can be given at fixed doses

Less Less impact on Improved

labour-intensive patients daily life compliance

Reduced Improved Improved

administrative quality of life efficacy
costs and safety
New drugs in phase III development
directly targeting coagulation factors
TF VIIa

Initiation
X IX

Va
Propagation =
Xa IXa
thrombin-generation
phase
Rivaroxaban II Prothrombin
Prothrombinase
Inactive factor apixaban complex
edoxaban
Active factor and others
Dabigatran Thrombin
Transformation IIa
and others
Catalysis

Clot formation Fibrinogen Fibrin

TF, tissue factor
Adapted from: Kubitza D, Haas S. Expert Opin Investig Drugs 2006
Rivaroxaban: Phase III Studies
Programme in VTE Treatment
 EINSTEIN DVT and PE: Study Outcomes
Primary efficacy outcome*
Symptomatic recurrent VTE: composite of recurrent DVT, non-fatal
PE or fatal PE

Principal safety outcome*

Combination of major and non-major clinically relevant bleeding

Secondary outcomes
All-cause mortality
Vascular events
Acute coronary syndrome, ischaemic stroke, transient ischaemic
attack or systemic embolism
Net clinical benefit
The composite of the primary efficacy outcome or major bleeding
*Adjudicated by a central independent and blinded adjudication committee
1. The EINSTEIN Investigators. N Engl J Med 2010;363:24992510;
2. The EINSTEINPE Investigators. N Engl J Med 2012; 366:12871297
EINSTEIN DVT
 EINSTEIN DVT: Study Design
Randomized, open-label, event-driven, non-inferiority study
Patients with confirmed acute symptomatic DVT without
symptomatic PE
88 primary efficacy outcomes needed

Treatment period: 3, 6 or 12 months

Day 1 Day 21
Rivaroxaban Rivaroxaban

30-day observation
N=3449

after treatment
Confirmed 15 mg bid 20 mg od

cessation
symptomatic DVT
without R
symptomatic PE
Enoxaparin (1.0 mg/kg) bid for at least 5 days,
plus VKA target INR 2.5 (INR range 2.03.0)

1. The EINSTEIN Investigators. N Engl J Med 2010;363:24992510

 EINSTEIN DVT: Primary Efficacy
Outcome Analysis
Rivaroxaban Enoxaparin/VKA
(n=1731) (n=1718)
n (%) n (%)
First symptomatic recurrent VTE 36 (2.1) 51 (3.0)
Recurrent DVT 14 (0.8) 28 (1.6)
Recurrent DVT + PE 1 (<0.1) 0 (0.0)
Non-fatal PE 20 (1.2) 18 (1.0)
Fatal PE/unexplained death where
4 (0.2) 6 (0.3)
PE cannot be ruled out
0.44 0.68 1.04

0 1.00 2.00
Hazard ratio
Rivaroxaban Rivaroxaban Rivaroxaban
superior non-inferior inferior
p=0.08 for superiority p<0.001 for non-inferiority
(two-sided) (one-sided)

ITT population
1. The EINSTEIN Investigators. N Engl J Med 2010;363:24992510
 EINSTEIN DVT: Primary Efficacy Outcome
Time to First Event
4.0
Cumulative event rate (%)

Enoxaparin/VKA (n=1718)

3.0
Rivaroxaban (n=1731)

2.0

HR=0.68; p<0.001 (non-inferiority)

1.0 RR=32%

0
0 30 60 90 120 150 180 210 240 270 300 330 360
Time to event (days)
Number of patients at risk

Rivaroxaban 1731 1668 1648 1621 1424 1412 1220 400 369 363 345 309 266

Enoxaparin/
1718 1616 1581 1553 1368 1358 1186 380 362 337 325 297 264
VKA

1. The EINSTEIN Investigators. N Engl J Med 2010;363:24992510

EINSTEIN DVT: Principal Safety Outcome (Composite
of Major or Non-major Clinically Relevant Bleeding)
14
Enoxaparin/VKA (n=1711)
Cumulative event rate (%)

12

10
Rivaroxaban (n=1718)
8

0
0 30 60 90 120 150 180 210 240 270 300 330 360
Time to event (days)
Number of patients at risk
Rivaroxaban 1718 1585 1538 1382 1317 1297 715 355 338 304 278 265 140
Enoxaparin/
1711 1554 1503 1340 1263 1238 619 338 321 287 268 249 118
VKA

1. The EINSTEIN Investigators. N Engl J Med 2010;363:24992510

 EINSTEIN DVT: Key Secondary and
Other Outcomes
Rivaroxaban Enoxaparin/VKA HR
Outcome
n/N (%) n/N (%) (95% CI)

Net clinical benefit: 0.67

(primary efficacy (0.470.95)
51/1731 (2.9) 73/1718 (4.2)
outcome plus major
bleeding) p=0.03

0.67
Total mortality 38/1731 (2.2) 49/1718 (2.9)
(0.441.02)

Cardiovascular 0.79
12/1718 (0.7) 14/1711 (0.8)
events (0.361.71)

1. The EINSTEIN Investigators. N Engl J Med 2010;363:24992510 (Supplementary Appendix)

 EINSTEIN DVT: Principal Safety
Outcome Analysis
Rivaroxaban Enoxaparin/VKA HR (95% CI)
(n=1718) (n=1711)
n (%) n (%) p-value
First major or non-major clinically relevant 0.97 (0.761.22)
139 (8.1) 138 (8.1)
bleeding p=0.77
0.65 (0.331.30)
Major bleeding 14 (0.8) 20 (1.2)
p=0.21

Contributing to death 1 (<0.1) 5 (0.3)

In a critical site 3 (0.2) 3 (0.2)

Associated with fall in haemoglobin

10 (0.6) 12 (0.7)
2 g/dl and/or transfusion of 2 units

Non-major clinically relevant bleeding 126 (7.3) 119 (7.0)

Safety population
1. The EINSTEIN Investigators. N Engl J Med 2010;363:24992510
 EINSTEIN DVT: Conclusions
In patients who had acute symptomatic proximal DVT without
symptomatic PE, rivaroxaban showed:
Non-inferiority to LMWH/VKA for efficacy (HR=0.68; 95% CI
0.441.04; p<0.001)
Similar findings for principal safety outcome between the two
groups (HR=0.97; 95% CI 0.761.22; p=0.77)
Consistent efficacy and safety results irrespective of age, body
weight, gender, creatinine clearance and cancer
No evidence of liver toxicity
Oral rivaroxaban, 15 mg bid for 21 days followed by rivaroxaban
20 mg od, could provide clinicians and patients with a simple,
single-drug approach for the acute treatment of DVT
that potentially improves the benefitrisk profile of anticoagulation

1. The EINSTEIN Investigators. N Engl J Med 2010;363:24992510

EINSTEIN EXT Study
 EINSTEIN EXT: Study
Background
Treatment for index venous thromboembolic event
612 months anticoagulation

Equipoise
Continue Should anticoagulation
be stopped
Stop treatment
anticoagulation
or continue?

Routine coagulation
monitoring, with dose
adjustment and
attendant risk of
bleeding

EINSTEIN EXT
1. The EINSTEIN Investigators. N Engl J Med 2010;363:24992510
 EINSTEIN EXT: Study Design
Randomized, double-blind, placebo-controlled, event-driven
(n=30), superiority study

Confirmed
symptomatic Treatment period of 6 or 12 months
DVT or PE Day 1
completing
612 months of ~53%
rivaroxaban or
VKA in Rivaroxaban 20 mg od

observation
EINSTEIN VTE N=1197

30-day

period
programme
R
Placebo

Confirmed
symptomatic
DVT or PE ~47%
completing
612 months
of VKA

1. The EINSTEIN Investigators. N Engl J Med 2010;363:24992510

 EINSTEIN EXT: Major Outcomes
Primary efficacy outcome*1
Symptomatic recurrent VTE, i.e. composite of recurrent DVT, non-fatal PE or
fatal PE, or unexplained death where PE cannot be excluded

Principal safety outcome*1,2

Major bleeding, defined as overt bleeding associated with:
A fall in haemoglobin of 2 g/dl, or
A transfusion of 2 units of packed red blood cells or whole blood, or
Occurrence at a critical site: intracranial, intraspinal, intraocular,
pericardial, intra-articular, intramuscular with compartment syndrome,
retroperitoneal, or
Death

*Adjudicated by a central independent adjudication committee

1. The EINSTEIN Investigators. N Engl J Med 2010;363:24992510;
2. The EINSTEIN Investigators. N Engl J Med 2010;363:24992510 (Supplementary Appendix)
 Enduring Protection Against Recurrent VTE When
Treatment is Continued

Rivaroxaban Placebo
n/N (%) n/N (%)
13 8/602 42/594
12
Cumulative event rate (%)

(1.3) (7.1)
11 Placebo (n=594)
10
9
8 82%
7 RRR
6 8.2% ARR
HR: 0.18
5
4 (95% CI 0.090.39)
3 p<0.001
2
1 Rivaroxaban (n=602)
0
0 30 60 90 120 150 180 210 240 270 300 330 360
Time to event (days)
Number of patients at risk
Rivaroxaban 602 590 583 573 552 503 482 171 138 132 114 92 81
Placebo 594 582 570 555 522 468 444 164 138 133 110 93 85
Recurrent VTE measured in the ITT population; all analyses were based on the first event
1. The EINSTEIN Investigators. N Engl J Med 2010;363:24992510
 EINSTEIN EXT: Primary Efficacy
Outcome by Subgroup
Symptomatic recurrent VTE
Rivaroxaban Placebo HR (95% CI)
n/N (%) n/N (%)
Overall 8/602 (1.3) 42/594 (7.1)
Age
<65 years 4/360 (1.1) 23/374 (6.2)
6575 years 3/153 (2.0) 8/121 (6.6)
>75 years 1/89 (1.1) 11/99 (11.1)
Weight
70 kg 3/135 (2.2) 11/157 (7.0)
>7090 kg 4/264 (1.5) 10/246 (4.0)
>90 kg 1/187 (0.5) 18/177 (10.2)
Gender
Male 4/354 (1.1) 29/339 (8.6)
Female 4/248 (1.6) 13/255 (5.1)
0.1 1 10
Favours Favours
rivaroxaban placebo
ITT population
1. The EINSTEIN Investigators. N Engl J Med 2010;363:24992510 (Supplementary Appendix)
 EINSTEIN EXT: Primary Efficacy
Outcome by Subgroup
Symptomatic recurrent VTE
Rivaroxaban Placebo HR (95% CI)
n/N (%) n/N (%)
Overall 8/602 (1.3) 42/594 (7.1)
Creatinine clearance
80 ml/min 22/373 (5.9) 3/373 (0.8)
50<80 ml/min 2/134 (1.5) 9/122 (7.4)
<50 ml/min 1/37 (2.7) 6/49 (12.2)
Missing 2/58 (3.5) 5/50 (10.0)
Pretreatment
Rivaroxaban 1/171 (0.6) 13/158 (8.2)
VKA 6/429 (1.4) 28/434 (6.5)

0.1 1 10
Favours Favours
rivaroxaban placebo

ITT population
1. The EINSTEIN Investigators. N Engl J Med 2010;363:24992510 (Supplementary Appendix)
 EINSTEIN EXT: Major Bleeding
Rivaroxaban Placebo
(n=598) (n=590)
n (%) n (%)

Major bleeding 4 (0.7)* 0 (0)

Bleeding contributing to death 0 (0) 0 (0)

Bleeding in a critical site 0 (0) 0 (0)

Associated with fall in haemoglobin

4 (0.7) 0 (0)
2 g/dl and/or transfusion of 2 units

Gastrointestinal bleeding 3 (0.5) 0 (0)

Menorrhagia 1 (0.2) 0 (0)

Safety population; *p=0.11

1. The EINSTEIN Investigators. N Engl J Med 2010;363:24992510
 EINSTEIN EXT: Non-major Clinically
Relevant Bleeding
Rivaroxaban Placebo
(n=598) (n=590)
n (%) n (%)

Non-major clinically relevant bleeding 32 (5.4) 7 (1.2)

Urogenital/uterus 12 (2.0) 2 (0.3)

Nasal 8 (1.3) 1 (0.2)

Rectal/anal 6 (1.0) 2 (0.3)

Skin 4 (0.7) 2 (0.3)

Ear 1 (0.2) 0 (0)

Gastrointestinal 1 (0.2) 0 (0)

Surgical site 1 (0.2) 0 (0)

Safety population; some patients experienced more than one event

1. The EINSTEIN Investigators. N Engl J Med 2010;363:24992510
 EINSTEIN EXT: Other Outcomes
Rivaroxaban Placebo
(n=598) (n=590)
n (%) n (%)
Cardiovascular outcomes 3 (0.5) 4 (0.7)
STEMI 0 (0) 0 (0)
Unstable angina 3 (0.5) 1 (0.2)
Transient ischemic attack 0 (0) 1 (0.2)
Ischemic stroke 0 (0) 1 (0.2)
Non-CNS systemic embolism 0 (0) 1 (0.2)
Total mortality 1 (0.2) 2 (0.3)
PE, or PE not ruled out 1 (0.2) 1 (0.2)
Cancer 0 (0) 1 (0.2)
Unexplained death including
1 (0.2) 0 (0)
where PE cannot be excluded

ITT population
1. The EINSTEIN Investigators. N Engl J Med 2010;363:24992510
 EINSTEIN EXT: Conclusions
In patients who had completed 612 months of anticoagulation, rivaroxaban
showed:
An 82% RRR in the recurrence of VTE (HR=0.18; p<0.001)
Absolute risk reduction 5.8%; hence 15 patients need to be treated to
prevent one recurrent venous thromboembolic event
Low incidence of major bleeding (0.7%; p=0.11; NNH approximately 139)
Efficacy and safety results were consistent irrespective of bodyweight
and creatinine clearance
Modest increase in non-major clinically relevant bleeding (5.4% vs 1.2%)
No signal for liver toxicity
Oral rivaroxaban 20 mg od could provide clinicians and patients with a
simple and effective option for continued anticoagulant treatment

1. The EINSTEIN Investigators. N Engl J Med 2010;363:24992510

Real World Evidence for Rivaroxaban in VTE
 XALIA: A Prospective, Non-
interventional Study
Objective: collect real-life data in patients with acute DVT treated
with rivaroxaban or standard anticoagulation

Patients with Rivaroxaban for 3 months Primary

Type, dose
diagnosis of outcomes
and
acute DVT* duration of Major bleeding
Investigators to collect data (1 month
and with an drug used after end of
events,
at initial visit, at 1 month and symptomatic
indication for at treatment)
discretion then quarterly# recurrent VTE
anticoagulant
therapy for of attending and all-cause
physician Standard anticoagulation, e.g. mortality
3 months
initial treatment with LMWH/fondaparinux,
followed by VKA or
parenteral anticoagulation for 3 months
Final
assessment

ClinicalTrials.gov NCT01619007; *After PE EU licence, DVT with concomitant PE permitted; isolated PE excluded
#Data were collected at the initial visit and during routine follow-up visits or via mail, telephone, or email
Ageno W et al, Thromb J 2014;12:16
 EINSTEIN DVT and XALIA:
Rivaroxaban Outcomes
3 Characteristic 3

55.8 Age (years) 57.3

Incidence (% of patients)

2.1
2 57.4% Male 54.5% 2

19.4%
Previous
24.1%
1.4
VTE

1 0.8 Baseline 1
6.8%
active cancer
5.6% 0.7

Known
6.2% 6.0%
thrombophilia
0 0
Major Recurrent Major Recurrent
#
bleeding* VTE bleeding* VTE*
(14/1718) (36/1731) (19/2619) (37/2619)

*Safety population (patients taking 1 dose of study drug); #ITT analysis

The EINSTEIN Investigators, N Engl J Med 2010;363:24992510
 Summary
XALIA is a prospective, non-interventional study demonstrating safety
and effectiveness of a NOAC for the treatment of VTE in clinical
practice
Physicians used rivaroxaban in younger patients and those with
fewer risk factors for recurrence
Crude rates of major bleeding, recurrent VTE and all-cause
mortality were low
Propensity score-adjusted analyses: rivaroxaban showed similar
safety and effectiveness to standard anticoagulation
XALIA data are consistent with those from EINSTEIN DVT
Patients on rivaroxaban had a shorter duration of hospital stay